Objective: In vitro study compared the efficacy in remineralizing initial caries of dentifrice containing natural hydroxyapatite (natHAP), synthetic HAP (synHAP), and fluoride. Methods: Initial carious lesions were created on 105 bovine enamel blocks by 4-day demineralization in a microbial caries model inoculated and fed 3× daily with 10% sucrose (6 min/episode). The caries-bearing blocks were stratified across seven treatment groups (N = 15/group); 20% nat-nHAP tooth powder, 20% nat-nHAP toothpaste, 30% nat-nHAP toothpaste, 20% nat-microHAP toothpaste, 15% syn-nHAP, fluoride (1100 ppm) toothpaste (NaF), and artificial saliva (AS) were used, and the groups were subjected to 28-day remineralization using a standardized pH cycling model with a daily regimen consisting of three 2 min toothpaste slurry treatments and one 2 h acidic challenge, and AS storage for the rest of the day. Surface microhardness of each block was measured after demineralization and after remineralization. Statistical analyses were performed using a paired t-test and Tukey’s multiple comparison test. Results: All groups induced significant (p < 0.001) remineralization. The %Rem was significantly lower for AS (9.61 ± 6.17%) than 30% nat-nHAP (29.21 ± 16.47%) and fluoride (27.05 ± 10.9%) toothpastes. There were no significant differences in %Rem among the natHAP formulations or between natHap and synHAP formulations. Conclusions: Within the limitations of the present in vitro study, dentifrices based on natHAP or synHAP have comparable efficacy to standard fluoride toothpaste in remineralizing initial caries.